The research theme of the Indiana Alcohol Research Center (IARC) is Genetic Determinants of Alcohol Ingestion. We hypothesize that between- individual variability in response to the reinforcing/aversive actions of ethanol, in development of tolerance and dependence, and in ethanol and acetaldehyde metabolism underlies much of the individual differences in ethanol ingestive behavior and susceptibility to alcoholism. Furthermore, much of this variability is genetic in origin. The IARC has unique resources to pursue this kind of research. A team of investigators with broad-based expertise ranging from molecular genetics and cellular neurobiology to physiological and behavioral studies in experimental animals and humans will address the central theme of the Center. Research for the 5 core components, 4 research components and a pilot projects component will include: the association of genetic polymorphisms of human alcohol and aldehyde dehydrogenases to alcoholism and its complications; the heritability, sensitivity and repeatability of a variety of responses to ethanol (e.g., electroencephalogram, event related potential, neuropeptide secretion, stance stability, voice pattern, eye movement and various other physiological and cognitive measures) in mono- and dizygotic twins; the value of such responses as predictors of subsequent abusive drinking behavior; the functional and structural loci in brain that are influenced by ethanol in a heritable manner; the study of the neurotransmitter systems implicated in abnormal alcohol-seeking behavior in rats; the influence of specific genes (e.g., alcohol dehydrogenase) on responses to ethanol in transgenic mice; and selective breeding of mice for high and low alcohol preference. Core laboratory functions will include the production of selective bred high and low alcohol-preferring rats for research, development of polymorphic markers associated with candidate genes for study in experimental animals and humans, and support of research into the structure-function relationships of molecules important to alcohol metabolism and the actions of ethanol. The pilot projects component will promote new research directions and recruit new investigators.